In brief, the present invention discloses methods and compositions for the treatment of platinum and/or taxane chemotherapy-resistant or -refractory advanced ovarian cancer subjects by i.v. and/or oral administration of the silicon-containing highly lipophilic camptothecin derivative (HLCD), Karenitecin (also known as BNP1350; cositecan; 7-[(2′-trimethylsilyl)ethyl]-20(S) camptothecin).
I. Ovarian Cancer
It is estimated that gynecological malignancies account for approximately 18.6% of all new cancer cases diagnosed and approximately 15.3% of all cancer related deaths in women worldwide. Of the gynecological malignancies, ovarian carcinoma is the second most common malignancy after cervical cancer. In 2002, ovarian cancer accounted for 204,200 new cases and 124,700 deaths representing approximately 4.0% of new cancer cases and 4.2% of cancer related deaths in women. See, e.g., Modugno F. Ovarian cancer and polymorphisms in the androgen and progesterone receptor genes. Am. J. Epidemiol. 159(4):319-335 (2004).
In the United States, it is estimated that each year there will be at least approximately 22,400 new cases diagnosed and 15,300 deaths due to ovarian carcinoma, accounting for approximately 3.0% of all cancers in women and causing more deaths than any other cancer of the female reproductive system. See, e.g., American Cancer Society: Cancer Facts and Figures 2009. Atlanta, Ga. American Cancer Society 2009. Unfortunately, as ovarian carcinoma is generally asymptomatic and not uncommonly clinically presents in protean diagnostic dilemmas by poorly defined, non-specific symptoms; the majority of patients are diagnosed with advanced stage disease of this cancer. Although much research has been conducted over the past several decades, the outcome for patients with advanced stage ovarian cancer still remains poor, with a 5-year survival rate ranging from less than 10% to 35% for women with stage III or IV disease.
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle and non-specific, early on and even in later stages and may include: bloating, pelvic pain, frequent urination, and are easily confused with other illnesses. The three major histologic subtypes of ovarian carcinoma, based on pathologic and clinical features, include epithelial tumors, germ cell tumors, and sex cord-stromal tumors. The majority of ovarian cancers are epithelial in origin, accounting for 80% to 90% of ovarian malignancies. See, e.g., Karlan B Y, Markman M A, Eifel P J. Ovarian cancer, peritoneal carcinoma, and fallopian tube carcinoma. In: DeVita V T Jr, Hellman S, Rosenberg S A, eds. Cancer. Principles & Practice of Oncology. 9th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2011:1368-1391. The epithelial tumors arise from the surface epithelium or serosa of the ovary. In the majority of cases, malignant epithelial ovarian tumors disseminate throughout the peritoneal cavity after exfoliation of malignant cells from the surface of the ovary. Tumor spread also occurs via the lymphatics from the ovary, and spread to lymph nodes is common.
Ovarian cancer is a surgically-staged cancer that is staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system for cancer of the ovary. See, Benedet J L, Pecorelli S, Ngan H Y S, Hacker N F. The FIGO Committee on Gynecologic Oncology. Staging Classifications and Clinical Practice Guidelines of Gynaecological Cancers. 3rd ed. Elsevier; 2006:95-121. Tumors confined to the ovaries are classified as stage I. A tumor which involves one or both ovaries with pelvic extension is classified as stage II. A tumor which involves one or both ovaries with microscopically-confirmed peritoneal metastases outside the pelvis and/or regional lymph nodes metastasis is classified as stage III. Distant metastasis beyond the peritoneal cavity is classified as stage IV. Liver capsule metastasis is considered stage III, and liver parenchymal metastasis is considered stage IV.
II. Pharmacology of Platinum Compounds
The anti-neoplastic drug cisplatin (cis-diamminedichloroplatinum or “CDDP”), and related platinum based drugs including carboplatin and oxaliplatin, are widely used in the treatment of a variety of malignancies including, but not limited to, cancers of the ovary, lung, colon, bladder, germ cell tumors and head and neck. Platinum complexes are reported to act, in part, by aquation (i.e., to form reactive aqua species), some of which may predominate intracellularly, and subsequently form DNA intra-strand coordination chelation cross-links with purine bases, thereby cross-linking DNA, thereby interfering with its function. The currently accepted paradigm with respect to cisplatin's mechanism of action is that the drug induces its cytotoxic properties by forming a reactive monoaquo species that reacts with the exposed DNA major groove N7 nitrogen contained within the imidazole components of guanine and adenosine found in nuclear DNA to form intrastrand platinum-DNA adducts. However, the exact mechanism of action of cisplatin is not completely understood and remains a subject of continued research interest within the scientific community. Thus, this mechanism is believed to work predominantly through DNA intra-strand cross-links, and less commonly, through inter-strand cross-links, thereby disrupting the DNA structure and function, which is cytotoxic to cancer cells. Platinum-resistant cancer cells are resilient to the cytotoxic actions of these agents. Certain cancers exhibit intrinsic de novo natural resistance to the killing effects of platinum agents and undergo no apoptosis, necrosis or regression following initial platinum compound treatment. In contrast, other types of cancers exhibit cytotoxic sensitivity to platinum drugs, as evidenced by tumor regression following initial treatment, but subsequently develop an increasing level of platinum resistance, which is manifested as a reduced responsiveness and/or tumor growth following treatment with the platinum drug (i.e., “acquired resistance”). Accordingly, new chemotherapeutic agents are continually being sought which will effectively kill tumor cells, but that are also insensitive or less susceptible to tumor-mediated drug resistance mechanisms that are observed with other platinum agents.
The reaction for cisplatin hydrolysis is illustrated below in Scheme I:

In neutral pH (i.e., pH 7), deionized water, cisplatin hydrolyzes to monoaquo/monohydroxy platinum complexes, which is less likely to further hydrolyze to diaqua complexes. However, cisplatin can readily form monoaquo and diaqua complexes by precipitation of chloro ligand with inorganic salts (e.g., silver nitrate, and the like). Also, the chloro ligands can be replaced by existing nucleophile (e.g., nitrogen and sulfur electron donors, etc.) without undergoing aquation intermediates.
Cisplatin is relatively stable in human plasma, where a high concentration of chloride prevents aquation of cisplatin. However, once cisplatin enters a tumor cell, where a much lower concentration of chloride exists, one or both of the chloro ligands of cisplatin is displaced by water to form an aqua-active intermediate form (as shown above), which in turn can react rapidly with DNA purines (i.e., Adenine and Guanine) to form stable platinum-purine-DNA adducts.
Cisplatin enters the cell through both passive diffusion and by active transport. The pharmacological behavior of cisplatin is in part determined by hydrolysis reactions that occur once cisplatin is inside the cell where the chloride concentration is essentially zero in nearly all major body organs, including the ovary. In this intracellular milieu, one chlorine ligand is replaced by a water molecule to yield an aquated version of cisplatin. The aquated platinum can then react with a variety of intracellular nucleophiles. Cisplatin binds to RNA more extensively than to DNA and to DNA more extensively than to protein; however, all of these reactions are thought to occur intracellularly. Thus, upon administration, a chloride ligand undergoes slow displacement with water (an aqua ligand) molecules, in a process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is easily displaced, allowing cisplatin to coordinate a basic site in DNA. Subsequently, the platinum cross-links two bases via displacement of the other chloride ligand. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis, as well as by DNA transcription and replication. The damaged DNA elicits various DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. Most notable among the DNA changes are the 1,2-intrastrand cross-links with purine bases. These include 1,2-intrastrand d(GpG) adducts which form nearly 90% of the platinum adducts and the less common 1,2-intrastrand d(ApG) adducts. 1,3-intrastrand d(GpXpG) adducts may also occur, but are readily excised by the nucleotide excision repair (NER) mechanism. Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's activity. In some cases, replicative bypass of the platinum 1,2-d(GpG) crosslink can occur allowing the cell to faithfully replicate its DNA in the presence of the platinum cross link, but often if this 1,2-intrastrand d(GpG) crosslink is not repaired, it interferes with DNA replication ultimately resulting in apoptosis.
The formation of cisplatin-DNA adducts that interfere with DNA replication is illustrated in Scheme II:

Interaction with cellular proteins, particularly High Mobility Group (HMG) chromosomal domain proteins (which are involved with transcription, replication, recombination, and DNA repair), has also been advanced as a mechanism of interfering with mitosis, although this is probably not its primary method of action. It should also be noted that although cisplatin is frequently designated as an alkylating agent, it has no alkyl group and cannot carry out alkylating reactions. Accordingly, it is more accurately classified as an alkylating-like agent.
III. Pharmacology of Taxanes
Taxanes are semi-synthetically derived analogues of naturally occurring compounds derived from plants. In particular, taxanes are derived from the needles and twigs of the European yew (Taxus baccata), or the bark of the Pacific yew (Taxus brevifolia). The most widely known taxanes at this time are paclitaxel (Taxol and Abraxane) and docetaxel (Taxotere), which are widely utilized as antineoplastic agents.
Paclitaxel was discovered in the late 1970s, and was found to be an effective antineoplastic agent with a mechanism of action different from then-existing chemotherapeutic agents. Taxanes are recognized as effective agents in the treatment of many solid tumors which are refractory to other antineoplastic agents.
Paclitaxel has the molecular structure shown below as Formula (A):

Docetaxel is an analog of Paclitaxel, and has the molecular structure shown below as Formula (B):

Taxanes exert their biological effects on the cell microtubules and act to promote the polymerization of tubulin, a protein subunit of spindle microtubules. The end result is the inhibition of depolymerization of the microtubules, which causes the formation of stable and nonfunctional microtubules. This disrupts the dynamic equilibrium within the microtubule system, and arrests the cell cycle in the late G2 and M phases, which inhibits cell replication. Taxanes interfere with the normal function of microtubule growth and arrest the function of microtubules by hyper-stabilizing their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner.
Taxanes function as an anti-neoplastic agent by binding to the N-terminal 31 amino acid residues of the β-tubulin subunit in tubulin oligomers or polymers, rather than tubulin dimers. Unlike other anti-microtubule agents (e.g., vinca alkaloids) which prevent microtubule assembly, submicromolar concentrations of taxanes function to decrease the lag-time and shift the dynamic equilibrium between tubulin dimers and microtubules (i.e., the hyperpolymerization of tubulin oligomers) toward microtubules assembly and stabilize the newly formed microtubules against depolymerization. The microtubules which are formed are highly stable, thereby inhibiting the dynamic reorganization of the microtubule network. See, e.g., Rowinsky, E. K., et al., Taxol: The prototypic taxane, an important new class of antitumor agents. Semin. Oncol. 19:646 (1992). Tubulin is the “building block” of microtubules, the resulting microtubule/taxane complex does not have the ability to disassemble. Thus, the binding of taxanes inhibit the dynamic reorganization of the microtubule network. This adversely affects cell function because the shortening and lengthening of microtubules (i.e., dynamic instability) is necessary for their function as a mechanism to transport other cellular components. For example, during mitosis, microtubules position the chromosomes during their replication and subsequent separation into the two daughter-cell nuclei.
In addition, even at submicromolar concentrations, the taxanes also induce microtubule bundling in cells, as well as the formation of numerous abnormal mitotic asters (which unlike mitotic asters formed under normal physiological conditions, do not require centrioles for enucleation. Thus, the taxanes function to inhibit the proliferation of cells by inducing a sustained mitotic “block” at the metaphase-anaphase boundary at a much lower concentration than that required to increase microtubule polymer mass and microtubule bundle formation. See, e.g., Rao, S., et al., Direct photoaffinity labeling of tubulin with taxol. J. Natl. Cancer Inst. 84:785 (1992). It should be noted that many of the deleterious side-effects caused by the taxanes are due to the sustained mitotic “block” at the metaphase-anaphase boundary in normal (i.e., non-neoplastic cells).
In addition to stabilizing microtubules, the taxane, paclitaxel, may act as a “molecular sponge” by sequestering free tubulin, thus effectively depleting the cells supply of tubulin monomers and/or dimers. This activity may trigger the aforementioned apoptosis. One common characteristic of most cancer cells is their rapid rate of cell division. In order to accommodate this, the cytoskeleton of the cancer cell undergoes extensive restructuring. Paclitaxel is an effective treatment for aggressive cancers because it adversely affects the process of cell division by preventing this restructuring. Although non-cancerous cells are also adversely affected, the rapid division rate of cancer cells make them far more susceptible to paclitaxel treatment.
Further research has also indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called B-cell leukemia 2 (Bcl-2), thus arresting its function.
The molecular structure of taxanes are complex alkaloid esters consisting of a taxane system linked to a four-member oxetan ring at positions C-4 and C-5. The taxane rings of both paclitaxel and docetaxel, but not 10-deacetylbaccatin III, are linked to an ester at the C-13 position. Experimental and clinical studies have demonstrated that analogs lacking the aforementioned linkage have very little activity against mammalian tubulin. Moreover, the moieties at C-2′ and C-3′ are critical with respect to its full biological activity, specifically, for the anti-microtubule hyperpolymerization effect of taxane. The C-2′ —OH is of paramount importance for the activity of taxol and while the C-2′ —OH of taxol can be “substituted” by a sufficiently strong nucleophile (see, PCT/US98/21814; page 62, line 8-27) the biological activity would be greatly diminished. See, e.g., Lataste, H., et al., Relationship between the structures of Taxol and baccatine III derivatives and their in vitro action of the disassembly of mammalian brain. Proc. Natl. Acad. Sci. 81:4090 (1984). For example, it has been demonstrated that the substitution of an acetyl group at the C-2′ position markedly reduces taxane activity. See, e.g., Gueritte-Voegelein, F., et al., Relationships between the structures of taxol analogues and their antimitotic activity. J. Med. Chem. 34:992 (1991).
Taxanes are toxic compounds having a low therapeutic index which have been shown to cause a number of different toxic effects in patients. The most well-known and severe adverse effects of taxanes are neurotoxicity and hematologic toxicity, particularly anemia and severe neutropenia/thrombocytopenia. Additionally, taxanes also cause hypersensitivity reactions in a large percentage of patients; gastrointestinal effects (e.g., nausea, diarrhea and vomiting); alopecia; anemia; and various other deleterious physiological effects, even at the recommended dosages. These Taxane medicaments include, in a non-limiting manner, docetaxel or paclitaxel (including the commercially-available paclitaxel derivatives Taxol and Abraxane), polyglutamylated forms of paclitaxel (e.g., Xyotax), liposomal paclitaxel (e.g., Tocosol), and analogs and derivatives thereof.